Gut Microbiota Reshapes the Tumor Microenvironment and Affects the Efficacy of Colorectal Cancer Immunotherapy

ABSTRACT Background Colorectal cancer (CRC) is among the most prevalent malignant tumors in the digestive system and is the third leading cause of cancer‐related mortality. In recent years, immunotherapy has markedly enhanced the objective response and survival rates for CRC patients. However, the therapeutic efficacy of immunotherapy remains insufficient for the majority of proficient mismatch repair (pMMR) CRC patients, with 20% to 30% of deficient mismatch repair (dMMR) patients demonstrating poor responses or developing drug resistance. Increasing evidence underscores the critical role of intestinal microorganisms in modulating the effectiveness of immunotherapy, particularly in regulating the tumor microenvironment (TME). Methods This review investigates the differences in intestinal microbiota and TME between dMMR and pMMR CRC. It explores how intestinal microbial communities influence TME components, including immune cells, macrophages, and fibroblasts, thereby impacting the response to immunotherapy. Conclusion Intestinal microorganisms play a critical role in the effectiveness of immunotherapy. Variations in intestinal microbiota and the TME among patients with different mismatch repair deficiencies can significantly influence the efficacy of immune checkpoint inhibitors. Modulating the intestinal microbiota has the potential to enhance the therapeutic response of CRC to immunotherapy.